Fluid flow control through microfluidic and capillary devices has been problematic. Application of macro-scale flow control techniques, such as, e.g., mechanical valving and discrete pumping, can be complex, expensive, difficult to manufacture, and poorly functional in micro-scale applications. Some micro-scale cartridges address flow control issues using wicking, centrifugation, hydrophobic treated surfaces, electrowetting, and the like, to influence flow of fluids through cartridge channels. Still, problems arise or remain in many micro-flow applications.
Many samples of interest, e.g., in bioassays include substantial amounts of particulate that must be removed to prevent interference in the assay reactions and to avoid clogging of assay device channels. The use of filter materials to remove particulate is known in the prior art. For example, in one configuration, filters are provided with a long lateral flow path, such as is described in “Devices for Incorporating Filters for Filtering Fluid Samples”, U.S. Pat. No. 6,391,265, to Buechler, et al. Buechler applies sample fluid to one end of a planar filter and collects filtrate at the other end of the same filter. However, this single filter technology has the disadvantage the same filter dealing with the gross particulate of the sample also has to handle the final fine filtration. Moreover, the long filter path can cause undue delay in filtration and loss of sample to excess dead volume.
Another issue often encountered in assay cartridges concerns how to control residence time in reaction chambers. It can be desirable to have sample flow quickly into contact with analytical reagents, but then linger for adequate mixing and completion of reaction kinetics. In some embodiments, flows can be stopped by increasing the contact angle of the fluid at the surface (e.g., by increasing the channel diameter or by coating the channel surface with a hydrophobic material), but the flows are not readily resumed without application of an external force. For example, electrowetting forces can be applied to resume flow, as disclosed in U.S. Pat. No. 7,117,807. Electro-capillarity or electrowetting (EW) is based on the observation that electrostatic forces can change surface tension of a fluid at a near-by surface. However, such control requires incorporation of electrodes and control electronics into the assay system. Alternately, as described in U.S. Pat. No. 6,905,882, a flow from a reaction chamber can be delayed by a time gate made up of a hydrophobic surface at the exit port of the chamber. Reaction product is released from the reaction chamber when the hydrophobic stop surface is rendered hydrophilic by constituents of the reaction liquid. However, consistent flow delay can require unchanging fluid compositions, consistent temperatures, consistent manufacturing, etc.
Retention of reagents on plastic surfaces of analytical cartridges can be a problem. The surfaces, e.g., of polystyrene, can have insufficient reagent concentration and too brief a residence time as analyte solutions flow past. In some cases reaction or detection regions have been stuffed full of capillary materials, however, this can overly inhibit flow and block viewing angles for detection devices.
Many assay cartridges are assembled by fusing several layered components. With such devices, it can be difficult to control leakage between layers or to control capillary creeping along interfaces of imperfectly fitting layers. Moreover, bubbles or particles in narrow channels between the layers can cause blockage.
Multi-assay concepts exist, but they are not optimized for the small sample size commonly encountered in the microfluidic or massive screening environments. For example in the multi-assay system of U.S. Pat. No. 7,347,972, completion of five different assays requires five times as much sample as one assay. In U.S. Patent application 2005/0249633, multiple assays require sample fluid to flow to multiple dead end arms of a branched channel system, requiring additional sample for each arm and setting the stage for problematic or impossible filling, rinsing and scanning for the isolated analytical regions of the cartridge.
In view of the above, a need exists for capillary/microfluidic cartridges that can readily and efficiently provide sample for analysis without particles. It would be desirable to have assay cartridges that can efficiently provide multiple analysis results from one small sample. It would be desirable to have restrictive flow channels that are not sensitive to blockage by bubbles. There would be benefits in cartridges with high reagent concentrations without flow restriction. A simple reaction chamber residence time controller that is easy to manufacture, without the need for high assembly tolerances, and without the need for input of external timing forces, would be appreciated in the art. The present invention provides these and other features that will be apparent upon review of the following.